ABSTRACT/SUMMARY Methamphetamine (MA) use disorder (MUD) is a significant public-health concern. The number of past month MA users increased dramatically (i.e., 60%) between 2010 and 2014, while the number of overdose deaths involving MA increased 2.7-fold. In 2015, 872,000 individuals had MUD, which accounted for over 8% of treatment admissions in the USA and 225,000 individuals initiated MA use. Dramatic increases in MA seizures by law-enforcement agencies suggest the problem may worsen. MUD is characterized by perturbations in central monoamine systems making them logical targets for developing a pharmacotherapeutic MUD. The proposed research will demonstrate the initial efficacy of an innovative strategy for MUD: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are under development, but are not yet available. Triple monoamine-uptake inhibition can, however, be achieved by combining medications. Duloxetine (DUL) has high affinity for the serotonin (5HT) and norepinephrine (NE) transporters (ki = 0.8 and 7.5 nM, respectively), but lower affinity for the dopamine (DA) transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM), but lower affinity for the 5HT and NE transporters (ki ? 10,000 and 339 nM, respectively). Combine DUL and MTH will functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non- treatment-seeking MUD participants are randomized to different maintenance doses of DUL (i.e., 0, 60 mg/day; DUL is a between-subject factor). Participants (N=14) in each DUL cohort will be maintained concurrently on MTH (i.e., 0, 20, 40, 60 mg/day; MTH is a within-subject factor). MA self-administration will be determined after participants in each DUL cohort are maintained for four days on each of the MTH doses (i.e., MA is a within- subject factor). MA self-administration is the primary outcome measure because the ability to attenuate drug reinforcement is a reliable predictor of an effective pharmacotherapy. We predict DUL-MTH combinations will produce an additive or supra-additive reduction in MA self-administration relative to the drugs alone. Innovations include: 1) testing a novel pharmacological strategy; 2) testing a combination of marketed drugs as opposed to waiting for novel compounds to be available for testing in humans, thereby impacting clinical research and practice more quickly; 3) use of a sophisticated drug self-administration procedure; 4) testing different doses of DUL and MTH alone and in combination to identify the most efficacious dose combination which increases the probability of success when advanced to a clinical trial; 5) providing three-way (i.e., MA, DUL, MTH) safety data that is often required by the FDA for approval of medication combinations for substance-use disorders; and 6) providing the impetus for conducting Phase II clinical trials to further demonstrate the efficacy of DUL-MTH combinations. This project will have a significant impact on clinical research and practice by identifying a first-in class pharmacotherapeutic for MUD.